Summary:We have tested whether small intraischemic variations in brain temperature influence the outcome of transient ischemia. To measure brain temperature, a ther mocouple probe was placed stereotaxically into the left dorsolateral striatum of rats prior to 20 min of four-vessel occlusion. Rectal temperature was maintained at 36-37°C by a heating lamp, and striatal temperature prior to ischemia was 36°C in all animals. Six animal subgroups were investigated, including rats whose intraischemic striatal brain temperature was not regulated, or was maintained at 33, 34, 36, or 39°C. Postischemic brain tem perature was regulated at 36°C, except for one group in which brain temperature was lowered from 36°C to 33°C during the first hour of recirculation. Energy metabolites were measured at the end of the ischemic insult, and his topathological evaluation was carried out at 3 days after ischemia. Intraischemic variations in brain temperature had no significant influence on energy metabolite levels measured at the conclusion of ischemia: Severe depletion of brain ATP, phosphocreatine, glucose, and glycogen and elevation of lactate were observed to a similar degree in all experimental groups. The histopathological conse quences of ischemia, however, were markedly influenced by variations in intraischemic brain temperature. In the Despite the utility of small animal models of global ischemia, several groups have noted vari ability of outcome from animal to animal (Payan et aI., 1965;Furlow, 1982; Blomqvist et aI., 1984; Harrison et aI., 1985; Vibulsresth et aI., 1987). Al though these variations, in part, may be the conse quence of differences in the severity of ischemia it- 729hippocampus, CA I neurons were consistently damaged at 36°C, but not at 34°C. Within the dorsolateral striatum, ischemic cell change was present in 100% of the hemi spheres at 36°C, but in only 50% at 34°C. Ischemic neu rons within the central zone of striatum were not ob served in any rats at 34°C, but in all rats at 36°C. In rats whose striatal temperature was not controlled, brain tem perature fell from 36 to 30-31°C during the ischemic in sult. In this group, no ischemic cell change was seen within striatal areas and was only inconsistently docu mented within the CAl hippocampal region. These re sults demonstrate that (a) rectal temperature unreliably reflects brain temperature during ischemia; (b) despite severe depletion of brain energy metabolites during isch emia at all temperatures, small increments of intra ischemic brain temperature markedly accentuate histo pathological changes following 3-day survival; and (c) brain temperature must be controlled above 33°C in order to ensure a consistent histopathological outcome. Low ering of the brain temperature by only a few degrees during ischemia confers a marked protective effect. Key Words: Ischemia-Brain temperature-Rats-Hypo thermia.self, other factors not directly related to the pri mary insult may also play an important role in determining the ultimate histopathological out come.Recen...

We have used a photochemical reaction in vivo to induce reproducible thrombosis leading to cerebral infarction in rats. After the intravenous injection of rose bengal, a potent photosensitizing dye, an ischemic lesion was formed by irradiating the left parietal convexity of the exposed skull for 20 minutes with green light (560 nm) from a filtered xenon arc lamp. Animals were allowed to survive from 30 minutes to 15 days after irradiation. Early microscopic alterations within the irradiated zone included the formation of thrombotic plugs and adjacent red blood cell stasis within pial and parenchymal vessels. Scanning electron microscopy revealed frequent platelet aggregates adhering to the vascular endothelium, often resulting in vascular occlusion. Carbon-black brain perfusion demonstrated that occlusion of vascular channels progressed after irradiation and was complete within 4 hours. Histopathological examination at 1, 5, and 15 days revealed that the associated infarct evolved reproducibly through several characteristic stages, including a phase of massive macrophage infiltration. Although cerebral infarction in this model is initiated by thrombosis of small blood vessels, the fact that the main pathological features of stroke are consistently reproduced should permit its use in assessing treatment regimens. Further, the capability of producing infarction in preselected cortical regions may facilitate the study of behavioral, functional, and structural consequences of acute and chronic stroke.

Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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We have demonstrated previously that mild intraischemic hypothermia confers a marked protective effect on the final histopathological outcome. The present study was carried out to evaluate whether this protective effect involves changes in the degree of local cerebral blood flow reductions, tissue accumulation of free fatty acids, or alterations in the extracellular release of glutamate and dopamine. Rats whose intraischemic brain temperature was maintained at 36° C, 33° C, or 30° C were subjected to 20 minutes of ischemia by four-vessel occlusion combined with systemic hypotension. Levels of local cerebral blood flow, as measured autoradiographically, were reduced uniformly in all experimental animals at the end of the ischemic period. Cortical and striatal free fatty acid levels were measured at the end of ischemia by gas chromatography after tissue extraction and separation by thin layer chromatography. A massive ischemia-induced accumulation of individual free fatty acids was observed in animal groups whose intraischemic brain temperature was maintained at either 36° C or 30° C. Extracellular neurotransmitter levels were measured by microdialysis; the perfusate was collected before, during, and after ischemia. In rats whose intraischemic brain temperature was maintained at 36° C, dopamine and glutamate increased significantly during ischemia and the early period of recirculation (by 500-fold and sevenfold, respectively). In animals whose brain temperature was maintained at 33° C and 30° C, the release of glutamate was completely inhibited, and the release of dopamine was significantly attenuated (by 60%). These results suggest that mild intraischemic hypothermia does not affect the ischemia-induced local cerebral blood flow reduction or free fatty acid accumulation. Received December 27, 1988; accepted March 7, 1989. hypothermia has been attributed mainly to a decrease in brain energy demands, energy failure during the ischemic insult, or both. Recently, we have demonstrated that relatively modest decrements (2° C) in brain temperature during the ischemic insult markedly attenuate neuronal damage in vulnerable brain regions such as the hippocampus or striatum. 8 However, the degree of high-energy phosphate depletion and lactate accumulation at the end of the ischemic insult were not affected by these temperature variations. These results suggest that a moderate reduction in intraischemic brain temperature affects a different consequence of brain ischemia that is important for the development of neuronal damage in these selectively vulnerable brain regions.Neurotransmitter release has been implicated in the pathophysiology of brain damage within hippocampal and striatal areas after ischemia.